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Quantitative approaches for assessing dose–response relationships in genetic toxicology studies
Author(s) -
Gollapudi B.B.,
Johnson G.E.,
Hernandez L.G.,
Pottenger L.H.,
Dearfield K.L.,
Jeffrey A.M.,
Julien E.,
Kim J.H.,
Lovell D.P.,
MacGregor J.T.,
Moore M.M.,
van Benthem J.,
White P.A.,
Zeiger E.,
Thybaud V.
Publication year - 2013
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.21727
Subject(s) - genotoxicity , methyl methanesulfonate , micronucleus test , ethyl methanesulfonate , toxicology , in vivo , point of delivery , risk assessment , computational biology , toxicogenomics , biology , mode of action , pharmacology , statistics , genetics , toxicity , computer science , mathematics , medicine , gene , mutation , dna repair , gene expression , computer security , agronomy
Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous “yes” or “no” manner without analysis of dose–response relationships. This article is based upon the work of an international multi‐sector group that examined how quantitative dose–response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose–response curves and deriving point‐of‐departure (POD) metrics (i.e., the no‐observed‐genotoxic‐effect‐level (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo . These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL 10 ) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose–response data. Environ. Mol. Mutagen., 2013. © 2012 Wiley Periodicals, Inc.